Arylindenopyridines and arylindenopyrimidines and related therapeutic and prophylactic methods

ABSTRACT

This invention provides novel arylindenopyridines and arylindenopyrimidines of the formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , and X are as defined above, and pharmaceutical compositions comprising same, useful for treating disorders ameliorated by antagonizing adenosine A2a receptors. This invention also provides therapeutic and prophylactic methods using the instant compounds and pharmaceutical compositions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of co-pending application Ser. No. 11/170,484 filed Jun. 29, 2005 which is divisional of application Ser. No. 10/678,562 filed Oct. 3, 2003 which is a continuation-in-part of co-pending application Ser. No. 10/259,139, filed on Sep. 27, 2002, which is a continuation-in-part of co-pending application Ser. No. 10/123,389, filed on Apr. 16, 2002, both of which are incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to novel arylindenopyridines and arylindenopyrimidines and their therapeutic and prophylactic uses. Disorders treated and/or prevented using these compounds include neurodegenerative and movement disorders ameliorated by antagonizing Adenosine A2a receptors.

BACKGROUND OF THE INVENTION Adenosine A2a Receptors

Adenosine is a purine nucleotide produced by all metabolically active cells within the body. Adenosine exerts its effects via four subtypes of cell-surface receptors (A1, A2a, A2b and A3), which belong to the G protein coupled receptor superfamily (Stiles, G. L. Journal of Biological Chemistry, 1992, 267, 6451). A1 and A3 couple to inhibitory G protein, while A2a and A2b couple to stimulatory G protein. A2a receptors are mainly found in the brain, both in neurons and glial cells (highest level in the striatum and nucleus accumbens, moderate to high level in olfactory tubercle, hypothalamus, and hippocampus etc. regions) (Rosin, D. L.; Robeva, A.; Woodard, R. L.; Guyenet, P. G.; Linden, J. Journal of Comparative Neurology, 1998, 401, 163).

In peripheral tissues, A2a receptors are found in platelets, neutrophils, vascular smooth muscle and endothelium (Gessi, S.; Varani, K.; Merighi, S.; Ongini, E.; Borea, P. A. British Journal of Pharmacology, 2000, 129, 2). The striatum is the main brain region for the regulation of motor activity, particularly through its innervation from dopaminergic neurons originating in the substantia nigra. The striatum is the major target of the dopaminergic neuron degeneration in patients with Parkinson's Disease (PD). Within the striatum, A2a receptors are co-localized with dopamine D2 receptors, suggesting an important site for the integration of adenosine and dopamine signaling in the brain (Fink, J. S.; Weaver, D. R.; Rivkees, S. A.; Peterfreund, R. A.; Pollack, A. E.; Adler, E. M.; Reppert, S. M. Brain Research Molecular Brain Research, 1992, 14, 186).

Neurochemical studies have shown that activation of A2a receptors reduces the binding affinity of D2 agonist to their receptors. This D2R and A2aR receptor-receptor interaction has been demonstrated in striatal membrane preparations of rats (Ferre, S.; von Euler, G.; Johansson, B.; Fredholm, B. B.; Fuxe, K. Proceedings of the National Academy of Sciences of the United States of America, 1991, 88, 7238) as well as in fibroblast cell lines after transfected with A2aR and D2R cDNAs (Salim, H.; Ferre, S.; Dalal, A.; Peterfreund, R. A.; Fuxe, K.; Vincent, J. D.; Lledo, P. M. Journal of Neurochemistry, 2000, 74, 432). In vivo, pharmacological blockade of A2a receptors using A2a antagonist leads to beneficial effects in dopaminergic neurotoxin MPTP(1-methyl-4-pheny-1,2,3,6-tetrahydropyridine)-induced PD in various species, including mice, rats, and monkeys (Ikeda, K.; Kurokawa, M.; Aoyama, S.; Kuwana, Y. Journal of Neurochemistry, 2002, 80, 262). Furthermore, A2a knockout mice with genetic blockade of A2a function have been found to be less sensitive to motor impairment and neurochemical changes when they were exposed to neurotoxin MPTP (Chen, J. F.; Xu, K.; Petzer, J. P.; Staal, R.; Xu, Y. H.; Beilstein, M.; Sonsalla, P. K.; Castagnoli, K.; Castagnoli, N., Jr.; Schwarzschild, M. A. Journal of Neuroscience, 2001, 21, RC143).

In humans, the adenosine receptor antagonist theophylline has been found to produce beneficial effects in PD patients (Mally, J.; Stone, T. W. Journal of the Neurological Sciences, 1995, 132, 129). Consistently, recent epidemiological study has shown that high caffeine consumption makes people less likely to develop PD (Ascherio, A.; Zhang, S. M.; Hernan, M. A.; Kawachi, I.; Colditz, G. A.; Speizer, F. E.; Willett, W. C. Annals of Neurology, 2001, 50, 56). In summary, adenosine A2a receptor blockers may provide a new class of antiparkinsonian agents (Impagnatiello, F.; Bastia, E.; Ongini, E.; Monopoli, A. Emerging Therapeutic Targets, 2000, 4, 635).

SUMMARY OF THE INVENTION

This invention provides a compound having the structure of Formula I or II

-   -   or a pharmaceutically acceptable salt thereof, wherein     -   (a) R₁ is selected from the group consisting of         -   (i) —COR₅, wherein R₅ is selected from H, optionally             substituted C₁₋₈ straight or branched chain alkyl,             optionally substituted aryl and optionally substituted             arylalkyl;             -   wherein the substituents on the alkyl, aryl and                 arylalkyl group are selected from C₁₋₈ alkoxy,                 phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy,                 amino, cyano, carboalkoxy, or NR₇R₈ wherein R₇ and R₈                 are independently selected from the group consisting of                 hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇                 cycloalkyl, benzyl, aryl, or heteroaryl or NR₇R₈ taken                 together form a heterocycle or heteroaryl;         -   (ii) COOR₅, wherein R₅ is as defined above;         -   (ii) cyano;         -   (iii) —CONR₉R₁₀ wherein R₉ and R₁₀ are independently             selected from H, C₁₋₈ straight or branched chain alkyl, C₃₋₇             cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl,             alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and             heterocyclyl;             -   wherein the alkyl, cycloalkyl, alkoxy, acyl,                 alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and                 heterocyclyl groups may be substituted with carboxyl,                 alkyl, aryl, substituted aryl, heterocyclyl, substituted                 heterocyclyl, heteroaryl, substituted heteroaryl,                 hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,                 amino, alkoxy or arylalkyl, or R₉ and R₁₀ taken together                 with the nitrogen to which they are attached form a                 heterocycle or heteroaryl group;         -   (v) optionally substituted C₁₋₈ straight or branched chain             alkyl;             -   wherein the substituents on the alkyl, group are                 selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy,                 halogen, p-tosyloxy, mesyloxy, amino, cyano,                 carboalkoxy, carboxyl, aryl, heterocyclyl, heteroaryl,                 sulfonyl, thiol, alkylthio, or NR₇R₈ wherein R₇ and R₈                 are as defined above;     -   (b) R₂ is selected from the group consisting of optionally         substituted alkyl, optionally substituted aryl, optionally         substituted heteroaryl, optionally substituted heterocyclyl and         optionally substituted C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, aryloxy,         C₁₋₈ alkylsulfonyl, arylsulfonyl, arylthio, C₁₋₈ alkylthio, or         —NR₂₄R₂₅         -   wherein R₂₄ and R₂₅ are independently selected from H, C₁₋₈             straight or branched chain alkyl, arylalkyl, C₃₋₇             cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl             or R₂₄ and R₂₅ taken together with the nitrogen form a             heteroaryl or heterocyclyl group,     -   (c) R₃ is from one to four groups independently selected from         the group consisting of:         -   hydrogen, halo, C₁₋₈ straight or branched chain alkyl,             arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄             carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen,             nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl,             heteroaryl, and heterocyclyl, —NR₁₁R₁₂,             -   wherein R₁₁ and R₁₂ are independently selected from H,                 C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇                 cycloalkyl, carboxyalkyl, aryl, heteroaryl, and                 heterocyclyl or R₁₀ and R₁₁ taken together with the                 nitrogen form a heteroaryl or heterocyclyl group,         -   —NR₁₃COR₁₄,             -   wherein R₁₃ is selected from hydrogen or alkyl and R₁₄                 is selected from hydrogen, alkyl, substituted alkyl,                 C₁₋₃ alkoxyl, carboxyalkyl, aryl, arylalkyl, heteroaryl,                 heterocyclyl, R₁₅R₁₆N(CH₂)_(p)—, or R₁₅R₁₆NCO(CH₂)_(p)—,                 wherein R₁₅ and R₁₆ are independently selected from H,                 OH, alkyl, and alkoxy, and p is an integer from 1-6,                 wherein the alkyl group may be substituted with                 carboxyl, alkyl, aryl, substituted aryl, heterocyclyl,                 substituted heterocyclyl, heteroaryl, substituted                 heteroaryl, hydroxamic acid, sulfonamide, sulfonyl,                 hydroxy, thiol, alkoxy or arylalkyl, or R₁₃ and R₁₄                 taken together with the carbonyl form a carbonyl                 containing heterocyclyl group;     -   (d) R₄ is selected from the group consisting of hydrogen, C₁₋₆         straight or branched chain alkyl, benzyl         -   wherein the alkyl and benzyl groups are optionally             substituted with one or more groups selected from C₃₋₇             cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy,             trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro,             hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₇R₁₈,             aryl and heteroaryl,     -   —OR₁₇, and —NR₁₇R₁₈,         -   wherein R₁₇ and R₁₈ are independently selected from             hydrogen, and optionally substituted C₁₋₆ alkyl or aryl; and     -   (e) X is selected from C═S, C═O; CH₂, CHOH, CHOR₁₉; or CHNR₂OR₂₁         where R₁₉, R₂₀, and R₂₁ are selected from optionally substituted         C₁₋₈ straight of branched chain alkyl, wherein the substituents         on the alkyl group are selected from C₁₋₈ alkoxy, hydroxy,         halogen, amino, cyano, or NR₂₂R₂₃ wherein R₂₂ and R₂₃ are         independently selected from the group consisting of hydrogen,         C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl,         aryl, heteroaryl, or NR₂₂R₂₃ taken together from a heterocycle         or heteroaryl;     -   with the proviso that in a compound of Formula II when R₁ is a         cyano, then R₂ is not phenyl.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

This invention further provides a method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in a subject, comprising of administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in the subject.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of Formula I are potent small molecule antagonists of the Adenosine A2a receptors that have demonstrated potency for the antagonism of Adenosine A2a, A1, and A3 receptors.

Preferred embodiments for R₁ are COOR₅ wherein R₅ is an optionally substituted C₁₋₈ straight or branched chain alkyl. Preferably the alkyl chain is substituted with a dialkylamino group.

Preferred embodiments for R₂ are optionally substituted heteroaryl and optionally substituted aryl. Preferably, R₂ is an optionally substituted furan.

Preferred substituents for R₃ include hydrogen, halo, hydroxy, amino, trifluoromethyl, alkoxy, hydroxyalkyl chains, and aminoalkyl chains,

Preferred substituents for R₄ include NH₂ and alkylamino.

In a preferred embodiment, the compound is selected from the group of compounds shown in Tables 1 and 2 hereinafter.

More preferably, the compound is selected from the following compounds:

The compound of claim 1, formula I, wherein R₄ is amino.

-   2-amino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one

-   2-amino-4-phenyl-indeno[1,2-d]pyrimidin-5-one

-   2-amino-4-thiophen-2-yl-indeno[1,2-d]pyrimidin-5-one

-   2-amino-4-(5-methyl-furan-2-yl)-indeno[1,2-d]pyrimidin-5-one

-   2,6-diamino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one

-   9H-indeno[2,1-c]pyridine-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-

-   9H-indeno[2,1-c]pyridine-4-carboxylic acid,     3-amino-1-furan-2-yl-9-oxo-, 2-dimethylamino-ethyl ester

-   9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-phenyl-9-oxo-,     2-dimethylamino-ethyl ester

-   9H-indeno[2,1-c]pyridine-4-carboxylic acid,     3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-1-methyl-ethyl)-amide

-   9H-indeno[2,1-c]pyridine-4-carboxylic acid,     3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-ethyl)-methyl-amide

-   9H-indeno[2,1-c]pyridine-4-carboxylic acid,     3-amino-1-furan-2-yl-9-oxo-, 1-methyl-pyrrolidin-2-ylmethyl ester

The instant compounds can be isolated and used as free bases. They can also be isolated and used as pharmaceutically acceptable salts. Examples of such salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, palmoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.

This invention also provides a pharmaceutical composition comprising the instant compound and a pharmaceutically acceptable carrier.

Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like. The typical solid carrier is an inert substance such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. Parenteral carriers include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like. All carriers can be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.

This invention further provides a method of treating a subject having a condition ameliorated by antagonizing Adenosine A2a receptors, which comprises administering to the subject a therapeutically effective dose of the instant pharmaceutical composition.

In one embodiment, the disorder is a neurodegenerative or movement disorder. Examples of disorders treatable by the instant pharmaceutical composition include, without limitation, Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.

In one preferred embodiment, the disorder is Parkinson's disease.

As used herein, the term “subject” includes, without limitation, any animal or artificially modified animal having a disorder ameliorated by antagonizing adenosine A2a receptors. In a preferred embodiment, the subject is a human.

Administering the instant pharmaceutical composition can be effected or performed using any of the various methods known to those skilled in the art. The instant compounds can be administered, for example, intravenously, intramuscularly, orally and subcutaneously. In the preferred embodiment, the instant pharmaceutical composition is administered orally. Additionally, administration can comprise giving the subject a plurality of dosages over a suitable period of time. Such administration regimens can be determined according to routine methods.

As used herein, a “therapeutically effective dose” of a pharmaceutical composition is an amount sufficient to stop, reverse or reduce the progression of a disorder. A “prophylactically effective dose” of a pharmaceutical composition is an amount sufficient to prevent a disorder, i.e., eliminate, ameliorate and/or delay the disorder's onset. Methods are known in the art for determining therapeutically and prophylactically effective doses for the instant pharmaceutical composition. The effective dose for administering the pharmaceutical composition to a human, for example, can be determined mathematically from the results of animal studies.

In one embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.001 mg/kg of body weight to about 200 mg/kg of body weight of the instant pharmaceutical composition. In another embodiment, the therapeutically and/or prophylactically effective dose is a dose sufficient to deliver from about 0.05 mg/kg of body weight to about 50 mg/kg of body weight. More specifically, in one embodiment, oral doses range from about 0.05 mg/kg to about 100 mg/kg daily. In another embodiment, oral doses range from about 0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment, from about 0.05 mg/kg to about 20 mg/kg daily. In yet another embodiment, infusion doses range from about 1.0 μg/kg/min to about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from about several minutes to about several days. In a further embodiment, for topical administration, the instant compound can be combined with a pharmaceutical carrier at a drug/carrier ratio of from about 0.001 to about 0.1.

DEFINITIONS AND NOMENCLATURE

Unless otherwise noted, under standard nomenclature used throughout this disclosure the terminal portion of the designated side chain is described first, followed by the adjacent functionality toward the point of attachment.

As used herein, the following chemical terms shall have the meanings as set forth in the following paragraphs: “independently”, when in reference to chemical substituents, shall mean that when more than one substituent exists, the substituents may be the same or different.

“Alkyl” shall mean straight, cyclic and branched-chain alkyl. Unless otherwise stated, the alkyl group will contain 1-20 carbon atoms. Unless otherwise stated, the alkyl group may be optionally substituted with one or more groups such as halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, carboxamide, hydroxamic acid, sulfonamide, sulfonyl, thiol, aryl, aryl(c₁-c₈)alkyl, heterocyclyl, and heteroaryl.

“Alkoxy” shall mean —O-alkyl and unless otherwise stated, it will have 1-8 carbon atoms.

The term “bioisostere” is defined as “groups or molecules which have chemical and physical properties producing broadly similar biological properties.” (Burger's Medicinal Chemistry and Drug Discovery, M. E. Wolff, ed. Fifth Edition, Vol. 1, 1995, Pg. 785).

“Halogen” shall mean fluorine, chlorine, bromine or iodine; “PH” or “Ph” shall mean phenyl; “Ac” shall mean acyl; “Bn” shall mean benzyl.

The term “acyl” as used herein, whether used alone or as part of a substituent group, means an organic radical having 2 to 6 carbon atoms (branched or straight chain) derived from an organic acid by removal of the hydroxyl group. The term “Ac” as used herein, whether used alone or as part of a substituent group, means acetyl.

“Aryl” or “Ar,” whether used alone or as part of a substituent group, is a carbocyclic aromatic radical including, but not limited to, phenyl, 1- or 2-naphthyl and the like. The carbocyclic aromatic radical may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Illustrative aryl radicals include, for example, phenyl, naphthyl, biphenyl, fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl, carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl, hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl, methoxyethylphenyl, acetamidophenyl, tolyl, xylyl, dimethylcarbamylphenyl and the like. “Ph” or “PH” denotes phenyl.

Whether used alone or as part of a substituent group, “heteroaryl” refers to a cyclic, fully unsaturated radical having from five to ten ring atoms of which one ring atom is selected from S, O, and N; 0-2 ring atoms are additional heteroatoms independently selected from S, O, and N; and the remaining ring atoms are carbon. The radical may be joined to the rest of the molecule via any of the ring atoms. Exemplary heteroaryl groups include, for example, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl, thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl, 2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl, benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide, benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl, benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl, indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or furo[2,3-b]pyridinyl), imidazopyridinyl (such as imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl), naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl, thienofuryl, thienopyridyl, thienothienyl, and furyl. The heteroaryl group may be substituted by independent replacement of 1 to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto, nitro, amino, C₁-C₈-alkyl, C₁-C₈-alkoxyl, C₁-C₈-alkylthio, C₁-C₈-alkyl-amino, di(C₁-C₈-alkyl)amino, (mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy, alkoxycarbonyl, C₁-C₈-alkyl-CO—O—, C₁-C₈-alkyl-CO—NH—, or carboxamide. Heteroaryl may be substituted with a mono-oxo to give for example a 4-oxo-1H-quinoline.

The terms “heterocycle,” “heterocyclic,” and “heterocyclo” refer to an optionally substituted, fully or partially saturated cyclic group which is, for example, a 4- to 7-membered monocyclic, 7- to 1′-membered bicyclic, or 10- to 15-membered tricyclic ring system, which has at least one heteroatom in at least one carbon atom containing ring. Each ring of the heterocyclic group containing a heteroatom may have 1, 2, or 3 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms, where the nitrogen and sulfur heteroatoms may also optionally be oxidized. The nitrogen atoms may optionally be quaternized. The heterocyclic group may be attached at any heteroatom or carbon atom.

Exemplary monocyclic heterocyclic groups include pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl; oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl; isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl; 2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl; 4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl; tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl; thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane; dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl; dihydroisoindolyl; dihydroquinazolinyl (such as 3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl; dihydrobenzothienyl; dihydrobenzothiopyranyl; dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl; isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and the like.

Substituted aryl, substituted heteroaryl, and substituted heterocycle may also be substituted with a second substituted-aryl, a second substituted-heteroaryl, or a second substituted-heterocycle to give, for example, a 4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.

Designated numbers of carbon atoms (e.g., C₁₋₈) shall refer independently to the number of carbon atoms in an alkyl or cycloalkyl moiety or to the alkyl portion of a larger substituent in which alkyl appears as its prefix root.

Unless specified otherwise, it is intended that the definition of any substituent or variable at a particular location in a molecule be independent of its definitions elsewhere in that molecule. It is understood that substituents and substitution patterns on the compounds of this invention can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

Where the compounds according to this invention have at least one stereogenic center, they may accordingly exist as enantiomers. Where the compounds possess two or more stereogenic centers, they may additionally exist as diastereomers. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention.

Some of the compounds of the present invention may have trans and cis isomers. In addition, where the processes for the preparation of the compounds according to the invention give rise to mixture of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared as a single stereoisomer or in racemic form as a mixture of some possible stereoisomers. The non-racemic forms may be obtained by either synthesis or resolution. The compounds may, for example, be resolved into their components enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation. The compounds may also be resolved by covalent linkage to a chiral auxiliary, followed by chromatographic separation and/or crystallographic separation, and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using chiral chromatography.

This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that these are only illustrative of the invention as described more fully in the claims which follow thereafter. Additionally, throughout this application, various publications are cited. The disclosure of these publications is hereby incorporated by reference into this application to describe more fully the state of the art to which this invention pertains.

EXPERIMENTAL DETAILS I. General Synthetic Schemes

Representative compounds of the present invention can be synthesized in accordance with the general synthetic methods described below and illustrated in the following general schemes. The products of some schemes can be used as intermediates to produce more than one of the instant compounds. The choice of intermediates to be used to produce subsequent compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

Procedures described in Schemes 1 to 7, wherein R_(3a), R_(3b), R_(3c), and R_(3d) are independently any R₃ group, and R₁, R₂, R₃, and R₄ are as described above, can be used to prepare compounds of the invention.

The substituted pyrimidines 1 can be prepared as shown in Scheme 1. The indanone or indandione 2 or the indene ester 3 can be condensed with an aldehyde to yield the substituted benzylidenes 4 (Bullington, J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.; Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper, J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). This is then condensed with guanidine carbonate to form the indenopyrimidine 1.

Alternatively, the pyrimidine compounds can be prepared as shown in Scheme 2. Sulfone 6 can be prepared by oxidation of the thiol ether 5 and the desired amines 7 can be obtained by treatment of the sulfone with aromatic amines.

Pyrimidines with substituents on the fused aromatic ring could also be synthesized by the following procedure (Scheme 3). The synthesis starts with alkylation of furan with allyl bromide to provide 2-allylfuran. Diels-Alder reaction of 2-allylfuran with dimethylacetylene dicarboxylate followed by deoxygenation (Xing, Y. D.; Huang, N. Z. J. Org. Chem. 1982, 47, 140) provided the phthalate ester 8. The phthalate ester 8 then undergoes a Claisen condensation with ethyl acetate to give the styryl indanedione 9 after acidic workup (Buckle, D. R.; Morgan, N. J.; Ross, J. W.; Smith, H.; Spicer, B. A. J. Med. Chem. 1973, 16, 1334). The indanedione 9 is then converted to the dimethylketene dithioacetal 10 using carbon disulfide in the presence of KF. Addition of Grignard reagents to the dithioacetal 10 and subsequent reaction with guanidine provides the pyrimidines 11 as a mixture of isomers.

Dihydroxylation and oxidation give the aromatic aldehydes 13 that can be reductively aminated to provide amines 14. The other isomer can be treated in a similar manner.

3-Dicyanovinylindan-1-one (15) (Scheme 5) was obtained using the published procedure (Bello, K. A.; Cheng, L.; Griffiths, J. J. Chem. Soc., Perkin Trans. II 1987, 815). Reaction of 3-dicyanovinylindan-1-one with an aldehyde in the presence of ammonium hydroxide produced dihydropyridines 16 (El-Taweel, F. M. A.; Sofan, M. A.; E.-Maati, T. M. A.; Elagamey, A. A. Boll. Chim. Farmac. 2001, 140, 306). These compounds were then oxidized to the corresponding pyridines 17 using chromium trioxide in refluxing acetic acid.

The ketone of pyridines 17 can be reduced to provide the benzylic alcohols 18. Alternatively, the nitriles can be hydrolyzed with sodium hydroxide to give the carboxylic acids 19 (Scheme 6).

The acids can then be converted to carboxylic esters 20 or amides 21 using a variety of methods. In general, the esters 20 are obtained by treatment with silver carbonate followed by an alkyl chloride or by coupling with diethylphosphoryl cyanide (DEPC) and the appropriate alcohol (Okawa, T.; Toda, M.; Eguchi, S.; Kakehi, A. Synthesis 1998, 1467). The amides 21 are obtained by coupling the carboxylic acid with the appropriate amine in the presence of DEPC or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl). Esters 20 can also be obtained by first reacting the carboxylic acids 19 with a dibromoalkane followed by displacement of the terminal bromide with an amine (Scheme 7).

II. Specific Compound Syntheses

Specific compounds which are representative of this invention can be prepared as per the following examples. No attempt has been made to optimize the yields obtained in these reactions. Based on the following, however, one skilled in the art would know how to increase yields through routine variations in reaction times, temperatures, solvents and/or reagents.

The products of certain syntheses can be used as intermediates to produce more than one of the instant compounds. In those cases, the choice of intermediates to be used to produce compounds of the present invention is a matter of discretion that is well within the capabilities of those skilled in the art.

Example 1 Synthesis of Benzylidene 4 (R₂=2-furyl, R_(3a)═F, R_(3b), R_(3d)═H)

A mixture of 3 (3.0 g, 11.69 mmol) and 2-furaldehyde (1.17 g, 12.17 mmol) in 75 mL of ethanol and 3 mL of concentrated hydrogen chloride was allowed to stir at reflux for 16 hours. The reaction was then cooled to room temperature, and the resulting precipitate was filtered off, washed with ethanol, diethyl ether, and air dried to afford 1.27 g (45%) of product.

Example 2 Synthesis of Indenopyrimidine 1 (R₂=2-furyl, R_(3a)═F, R_(3b), R_(3c), R_(3d)═H)

A mixture of 4 (0.5 g, 2.06 mmol), guanidine carbonate (0.93 g, 5.16 mmol), and 20.6 mL of 0.5 M sodium methoxide in methanol was stirred at reflux for 16 hours. The reaction mixture was cooled to room temperature, and diluted with water. The resulting precipitate was collected, washed with water, ethanol, diethyl ether, and then dried. Crude material was then purified over silica gel to afford 0.024 g (4%) of product. MS m/z 282.0 (M+H).

Example 3 Synthesis of 2-Amino-4-methanesulfonyl-indeno[1,2-d]pyrimidin-5-one

To a suspension of 5 (Augustin, M.; Groth, C.; Kristen, H.; Peseke, K.; Wiechmann, C. J. Prakt. Chem. 1979, 321, 205) (1.97 g, 8.10 mmol) in MeOH (150 mL) was added a solution of oxone (14.94 g, 24.3 mmol) in H₂O (100 mL). The mixture was stirred at room temperature overnight then diluted with cold H₂O (500 mL), made basic with K₂CO₃ and filtered. The product was washed with water and ether to give 0.88 g (40%) of sulfone 6. MS m/z 297.9 (M+Na).

Example 4 Synthesis of Aminopyrimidine 7 (R₂═NHPh, R₃═H)

A mixture of sulfone 6 (0.20 g, 0.73 mmol) and aniline (0.20 g, 2.19 mmol) in N-methylpyrrolidinone (3.5 mL) was heated to 100° C. for 90 minutes. After cooling to room temperature, the mixture was diluted with EtOAc (100 mL), washed with brine (2×75 mL) and water (2×75 mL), and dried over Na₂SO₄. After filtration and concentration in vacuo, the residue was purified by column chromatography eluting with 0-50% EtOAc in hexane to yield 0.0883 g (42%) of product 7. MS m/z 289.0 (M+H).

Example 5 Synthesis of Phthalate Ester 8

A 1.37 M hexanes solution of n-BuLi (53.6 mL, 73.4 mmol) was added to a cold, −78° C., THF solution (100 mL) of furan (5.3 mL, 73.4 mmol) and the reaction was then warmed to 0° C. After 1.25 h at 0° C. neat allyl bromide (7.9 mL, 91.8 mmol) was added in one portion. After 1 h at 0° C., saturated aqueous NH₄Cl was added and the layers were separated. The aqueous phase was extracted with EtOAc and the combined organics were washed with water and brine, dried over Na₂SO₄, and concentrated to give 4.6 g (58%) of 2-allylfuran which was used without further purification.

The crude allyl furan (4.6 g, 42.6 mmol) and dimethylacetylene dicarboxylate (5.2 mL, 42.6 mmol) were heated to 90° C. in a sealed tube without solvent. After 6 h at 90° C. the material was cooled and purified by column chromatography eluting with 25% EtOAc in hexanes to give 5.8 g (54%) of the oxabicycle as a yellow oil. MS m/z 251 (M+H).

Tetrahydrofuran (60 mL) was added dropwise to neat TiCl₄ (16.5 mL, 150.8 mmol) at 0° C. A 1.0 M THF solution of LiAlH₄ (60.3 mL, 60.3 mmol) was added dropwise, changing the color of the suspension from yellow to a dark green or black suspension. Triethylamine (2.9 mL, 20.9 mmol) was added and the mixture was refluxed at 75-80° C. After 45 min, the solution was cooled to rt and a THF solution (23 mL) of the oxabicycle (5.8 g, 23.2 mmol) was added to the dark solution. After 2.5 h at rt, the solution was poured into a 20% aq. K₂CO₃ solution (200 mL) and the resulting suspension was filtered. The precipitate was washed several times with CH₂Cl₂ and the filtrate layers were separated. The aqueous phase was extracted with CH₂Cl₂ and the combined organics were washed with water and brine, dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 25% EtOAc in hexanes to give 3.5 g (64%) of the phthalate ester 8 as a yellow oil. MS m/z 235 (M+H).

Example 6 Synthesis of Indanedione 9

A 60% dispersion of sodium hydride in mineral oil (641 mg, 16.0 mmol) was added to an EtOAc solution (3.5 mL) of the phthalate ester 8 (2.5 g, 10.7 mmol), and the resulting slurry was refluxed. After 1 h the solution became viscous so an additional 7.5 mL of EtOAc was added. After 4 h at reflux the suspension was cooled to rt and filtered to give a yellow solid. This solid was added portionwise to a solution of HCl (25 mL water and 5 mL conc. HCl) at 80° C. The suspension was heated for an additional 30 min at 80° C., cooled to rt, and filtered to give 1.2 g (60%) of the indanedione 9 as a yellow solid. MS m/z 187 (M+H).

Example 7 Synthesis of Dimethylketene Dithioacetal 10

Solid potassium fluoride (7.5 g, 129.1 mmol) was added to a 0° C. solution of indanedione 9 (1.2 g, 6.5 mmol) and CS₂ (0.47 mL, 7.8 mmol) in DMF (10 mL). The cold bath was removed and after 30 min neat iodomethane (1.00 mL, 16.3 mmol) was added. After 5 h at rt, the suspension was diluted with EtOAc and then washed with water and brine. The organic layer was dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 20% EtOAc in hexanes to give 1.4 g (75%) of the dimethylketene dithioacetal 10 as a yellow solid. MS m/z 291 (M+H).

Example 8 Synthesis of Pyrimidine 11 (R₂=Ph, R_(3a)═CHCHCH3, R_(3d)═H)

A 2.0 M solution of PhMgCl in THF (13 mL, 25.7 mmol) was added to a −78° C. solution of dimethylketene dithioacetal 10 (5.7 g, 19.8 mmol) in 200 mL of THF. After 3 h at −78° C., saturated aqueous NH₄Cl was added and the layers were separated. The aqueous layer was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 20% EtOAc in hexanes to give 4.9 g (77%) of the thioenol ether as a yellow solid. MS m/z 321 (M+H).

Solid guanidine hydrochloride (1.5 g, 15.3 mmol) was added to a solution of the thioenol ether (4.9 g, 15.3 mmol) and K₂CO₃ (2.6 g, 19.1 mmol) in 30 mL of DMF and the solution was heated to 80° C. After 6 h at 80° C., the solution was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 40% EtOAc in hexanes to give 4.6 g (96%) of the pyrimidine regioisomers 11 as yellow solids. MS m/z 314 (M+H).

Example 9 Synthesis of Aldehyde 13 (R₂=Ph)

Solid MeSO₂NH₂ (277 mg, 2.9 mmol) was added to a t-BuOH:H₂O (1:1) solution (30 mL) of AD-mix-α (4.0 g). The resulting yellow solution was added to an EtOAc solution (15 mL) of the pyrimidine (910 mg, 2.9 mmol). After 3 days, solid sodium sulfite (4.4 g, 34.9 mmol) was added. After stirring for 1.5 h, the heterogeneous solution was diluted with EtOAc and the layers were separated. The aqueous phase was extracted with EtOAc and the combined extracts were washed with water and brine, dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 100% EtOAc to give 710 mg (70%) of the intermediate diol 12. MS m/z 348 (M+H).

Solid HIO₄-2H₂O (933 mg, 4.1 mmol) was added to a 0° C. solution of diol 12 (710 mg, 2.1 mmol) in THF. After 1.5 h at 0° C., the solution was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO₃, water, and brine. The organic layer was dried over Na₂SO₄ and concentrated to give 603 mg (98%) of aldehyde 13 as a yellow solid that was used without further purification. MS m/z 302 (M+H).

Example 10 Synthesis of Amine 14 via Reductive Amination (R_(3a)═N(—CH₂CH₂OCH₂CH₂—)

Solid NaBH(OAc)₃ (53 mg, 0.25 mmol) was added to a solution of aldehyde 13 (50 mg, 0.17 mmol), morpholine (0.034 mL, 0.34 mmol), and AcOH (0.014 mL, 0.25 mmol) in 1 mL of THF. After 3 d the solution was filtered and concentrated. The resulting material was dissolved in CH₂Cl₂ and washed with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄, concentrated, and purified by column chromatography eluting with 0-10% MeOH in CH₂Cl₂ to give 38 mg (60%) of the amine 14 as a yellow solid. MS m/z 373 (M+H). The product was dissolved in a minimum amount of CH₂Cl₂ and treated with 1.0 M HCl in ether to obtain the hydrochloride salt.

Example 11 Cyclization to Form Dihydropyridine 16 (R₂=2-furyl, R₃═H)

To a solution of 3-dicyanovinylindan-1-one (4.06 g, 20.9 mmol) in 200 mL of ethanol was added 2-furaldehyde (3.01 g, 31.4 mmol) and 25 mL of conc. NH₄OH. The solution was heated to reflux for 2 h and allowed to cool to rt overnight. The mixture was concentrated in vacuo to remove ethanol. The residue was filtered and washed with water. The purple solid obtained was dried to yield 5.92 g (89%). MS m/z 290 (M⁺+1).

Example 12 Oxidation of Dihydropyridine 16 to Pyridine 17 (R₂=2-furyl, R₃═H, R₄═NH₂, R₅═CN, X═O)

To a refluxing solution of dihydropyridine 16 (5.92 g, 20.4 mmol) in acetic acid (100 mL) was added a solution of chromium (VI) oxide (2.05 g, 20.4 mmol) in 12 mL of water. After 10 minutes at reflux, the reaction was diluted with water until a precipitate started to form. The mixture was cooled to room temperature and filtered. The residue was washed with water to give 4.64 g (79%) of a brown solid. MS m/z 288 (M⁺+1).

Example 13 Reduction of Ketone 17 to Alcohol 18 (R₂=2-furl, R₃═H, R₄═NH, R₅═CN, X═H, OH)

To a 0° C. solution of ketone 17 (0.115 g, 0.40 mmol) in 12 mL of THF was added a 1.0 M LiAlH₄ solution in THF (0.40 mL, 0.40 mmol). The reaction was stirred at 0° C. for 1 h. The reaction was quenched by the addition of ethyl acetate (1.5 mL), water (1.5 mL), 10% aq. NaOH (1.5 mL), and saturated aq. NH₄Cl (3.0 mL). The mixture was extracted with ethyl acetate (3×35 mL), washed with brine, and dried over sodium sulfate. The remaining solution was concentrated to yield 0.083 g (72%) of a yellow solid. MS m/z 290 (M⁺+1).

Example 14 Hydrolysis of Nitrile 17 to Carboxylic Acid 19 (R₂=2-furyl, R₃═H, R₄═NH₂, R₅═COOH, X═O)

To a mixture of nitrile 17 (0.695 g, 2.42 mmol) and ethanol (30 mL) was added 5 mL of 35% aqueous sodium hydroxide. The resulting mixture was heated to reflux overnight. After cooling to rt, the solution was poured into water and acidified with 1 N HCl. The resulting precipitate was isolated by filtration and washed with water to yield 0.623 g (84%) of a brown solid. MS m/z 329 (M⁺+23).

Example 15 Synthesis of Carboxylic Ester 20 with Silver Carbonate (R₂=2-furyl, R₃═H, R₄═NH₂, R₅═CO₂CH₂CH₂NMe₂, X═O)

A suspension of carboxylic acid 19 (5.0 g, 16.3 mmol), silver carbonate (5.8 g, 21.2 mmol), and tetrabutylammonium iodide (1.5 g, 4.1 mmol) in 80 mL of DMF was heated to 90° C. After 1 h, the mixture was cooled to rt and 2-(dimethylamino)ethylchloride hydrochloride (2.4 g, 16.3 mmol) was added and the mixture was heated to 100° C. After 7 h, the reaction was filtered while hot, concentrated and purified by column chromatography eluting with 0-10% MeOH/CH₂Cl₂ to yield 0.160 g (3%) of a yellow solid. MS m/z 378 (M⁺+1). The product was dissolved in a minimum of dichloromethane and treated with 1.0 M HCl in ether to obtain the hydrochloride salt.

Example 16 Synthesis of Carboxylic Ester 20 with DEPC (R₂=2-furyl, R₃═H, R₄═NH₂, R₅═CO₂CH₂CH(—CH₂CH₂CH₂(Me)N—), X═O)

To a mixture of carboxylic acid 19 (0.40 g, 1.3 mmol) and (S)-1-methyl-2-pyrrolidinemethanol (0.50 mL, 3.9 mmol) in DMF (30 mL) was added 0.20 mL (1.3 mmol) of diethylphosphoryl cyanide and triethylamine (0.20 mL, 1.3 mmol). The reaction was stirred at 0° C. for one hour and then heated up to approximately 70° C. overnight. The reaction was then cooled to rt and diluted with ethyl acetate. The organic mixture was washed with saturated aqueous NaHCO₃, water, and brine. After being dried with sodium sulfate, the solution was concentrated. The residue was purified by column chromatography eluting with 10-100% ethyl acetate in hexane and then preparative TLC eluting with 2% MeOH in dichloromethane to yield 1.9 mg (0.4%) of a yellow solid. MS m/z 404 (M⁺+1).

Example 17 Synthesis of Carboxylic Amide 21 with DEPC (R₂=2-furyl, R₃═H, R₄═NH, R₅═CO₂CH₂CH(—CH₂CH₂CH₂(Me)N—), X═O)

To a mixture of carboxylic acid 19 (0.25 g, 0.82 mmol) and N,N,N′-trimethylethylenediamine (0.14 mL, 1.08 mmol) in DMF (20 mL) was added 0.12 mL (0.82 mmol) of diethylphosphoryl cyanide and triethylamine (0.11 mL, 0.82 mmol). The reaction was stirred at 0° C. for one hour and then heated up to approximately 60° C. overnight. The reaction was then cooled to rt and diluted with ethyl acetate. The organic mixture was washed with saturated aqueous NaHCO₃, water, and brine. After being dried with magnesium sulfate, the solution was concentrated. The residue was purified by column chromatography eluting with 0-10% methanol in dichloromethane and then preparative TLC eluting with 1% MeOH in dichloromethane to yield 3.3 mg (10%) of a yellow solid. MS m/z 391 (M⁺+1). The product was dissolved in a minimum of diethyl ether and treated with 1.0 M HCl in ether to obtain the hydrochloride salt.

Example 18 Synthesis of Carboxylic Amide 21 with EDCl (R₂=2-furyl, R₃═H, R₄═CON(—CH₂CH₂NMeCH₂CH₂—), X═O)

A mixture of carboxylic acid 19 (0.300 g, 0.979 mmol), N-methylpiperazine (0.295 g, 2.94 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.563 g, 2.94 mmol) 1-hydroxybenzotriazole hydrate (0.397 g, 2.94 mmol), triethylamine (0.298 g, 2.94 mmol) in DMF (8 mL) was stirred at rt overnight. The mixture was then diluted with water and extracted several times with ethyl acetate. The combined organics were washed twice with brine and then dried over sodium sulfate. The solution was concentrated and then purified by column chromatography to afford 0.092 g (2%) of solid. MS m/z 389 (M⁺+1). The product was treated with 1.0 M HCl in ether to obtain the hydrochloride salt.

Example 19 Synthesis of Carboxylic Ester 20 via a dibromoalkane (R₂=Ph, R₃═H, R₄═NH₂, R₅═CO₂CH₂CH₂CH₂NMe₂, X═O)

To a solution of carboxylic acid 19 (0.100 g, 0.32 mmol) in DMF (1.5 mL) was added 60% NaH dispersion in mineral oil (0.013 g, 0.32 mmol). After 10 min at rt, 1,3-dibromopropane (0.035 mL, 0.35 mmol) was added and the solution was stirred at rt for 17 h. After concentration, the residue was purified via column chromatography eluting with 40% ethyl acetate in hexanes to yield 0.014 g (9%) of a yellow solid. MS m/z 437 (M⁺+1).

To a solution of the yellow solid (0.014 mg, 0.03 mmol) in a sealed tube was added a 40% aqueous solution of dimethylamine (0.5 mL, 3.0 mmol). The tube was heated to 75° C. for 2 h before concentrating. The residue was purified by column chromatography eluting with 0-10% methanol in dichloromethane to yield 0.009 g (70%) of a yellow solid. MS m/z 402 (M⁺+1). The product was dissolved in a minimal amount of CH₂Cl₂ and treated with 1 N HCl in ether to obtain the hydrochloride salt.

Following the general synthetic procedures outlined above and in Examples 1-19, the compounds of Table 1 below were prepared.

TABLE 1

MS No. R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₄ X (M + 1) 1 4-MeOPh H H H H NH₂ CH₂ 290 2 4-MeOPh H H H H NH₂ CO 304 3 2-furyl H H H H NH₂ CO 264 4 2-furyl H H H H NH₂ CH₂ 250 5 3-pyridyl H H H H NH₂ CO 297 (+Na) 6 4-pyridyl H H H H NH₂ CO 275 7

H H H H NH₂ CO 281 8 4-ClC₆H₄ H H H H NH₂ CO 308 9 3-NO₂C₆H₄ H H H H NH₂ CO 319 10 Ph H H H H NH₂ CO 274 11 3-MeOC₆H₄ H H H H NH₂ CO 304 12 2-MeOC₆H₄ H H H H NH₂ CO 304 13 3-HOC₆H₄ H H H H NH₂ CO 290 14 2-thiophenyl H H H H NH₂ CO 302 15 3-thiophenyl H H H H NH₂ CO 302 16 2-furyl H Br H H NH₂ CO 342 17 2-furyl OH H H H NH₂ CO 280 18 SCH3 NH₂ H H H NH₂ CO 259 19 3-FC₆H₄ H H H H NCHNMe₂ CO 347 20 2-furyl NH₂ H H H NH₂ CO 279 21 2-furyl H H H NH₂ NH₂ CO 279 22 2-furyl H CF₃ H H NH₂ CO 332 23 2-furyl H H CF₃ H NH₂ CO 332 24 Ph H H H H NHMe CO 288 25 2-furyl H Cl Cl H NH₂ CO 332 26 2-furyl Cl H H Cl NH₂ CO 332 27 Ph H H H H N(CH₂)₂NEt₂ CO 373 28 3,4-F₂C₆H₃ H H H H NH₂ CO 310 29 3,5-F₂C₆H₃ H H H H NH₂ CO 310 30

H H H H NH₂ CO 305 31 3,4,5-F₃C₂H₂ H H H H NH₂ CO 340 (M + Na) 32 Ph

H H H NH₂ CO 348 33 Ph H H H

NH₂ CO 348 34

H H H H NH₂ CO 333 35 2-furyl H H Br H NH₂ CO 342/344 36 2-furyl H H H F NH₂ CO 282 37 2-furyl MeO H H H NH₂ CO 294 38 4-FC₆H₄ H H H H NH₂ CO 292 39 3-FC₆H₄ H H H H NH₂ CO 292 40 SO₂Me H H H H NH₂ CO 298 41 Sme H H H H NH₂ CO 266 42 Ome H H H H NH₂ CO 477 (2M + Na) 43 NHPh H H H H NH₂ CO 289 44 3-furyl H H H H NH₂ CO 264 45 5-methyl-2-furyl H H H H NH₂ CO 278 46 2-furyl OCH₂CH₂NHCO₂tBu H H H NH₂ CO 437 47 Ph H H H H Me CO 297 48 Ph H H H H OMe CO 291 49 Ph CH₂NMeCH₂CH₂NMe₂ H H H NH₂ CO 388 50 Ph

H H H NH₂ CO 386 51 Ph

H H H NH₂ CO 373 52 Ph CH₂NEt₂ H H H NH₂ CO 359 53 Ph

H H H NH₂ CO 371 54 Ph

H H H NH₂ CO 429 55 Ph

H H H NH₂ CO 443 56 Ph CH₂NMeCH₂CO₂Me H H H NH₂ CO 389 57 Ph

H H H NH₂ CO 401 58 Ph

H H H NH₂ CO 416 59 Ph

H H H NH₂ CO 414 60 Ph

H H H NH₂ CO 486 61 Ph

H H H NH₂ CO 422 62 Ph

H H H NH₂ CO 397

TABLE 2

MS No. X R₂ R_(3a) R_(3b) R_(3c) R_(3d) R₁ (M + 1) 63 CO 2-furyl H H H H CN 288 64 CO Ph H H H H CN 298 65 CO Ph H H H H COOH 315 (M − 1) 66 CO 3-furyl H H H H CN 288 67 CO 3-FC₆H₄ H H H H CN 316 68 CO 3-pyridyl H H H H CN 299 69 CO 2-furyl H H H H COOH 305 (M − 1) 70 CO 2-furyl H H H H CO₂CH₂CH₂NMe₂ 378 71 CO 4-FC₆H₄ H H H H CN 316 72 CO 2-thiophenyl H H H H CN 304 73 CO 3-thiophenyl H H H H CN 304 74 CO 3-MeOC₆H₄ H H H H CN 328 75 CO 2-imidazolyl H H H H CN 288 76 CO 2-furyl H H H H CONHCH₂CH₂NMe₂ 377 77 CO 2-furyl H H H H CONMeCH₂CH₂NMe₂ 391 78 CO 2-furyl H H H H CONHCHMeCH₂NMe₂ 391 79 CO 2-furyl F F F F CN 358 (M − 1) 80 CO 2-furyl H H H H

389 81 CO Ph H H H H CO₂CH₂CH₂NMe₂ 388 82 CO 2-furyl H H H H

404 83 CO Ph H H H H

457 84 CO Ph H H H H

444 85 CO Et H H H H CN 250 86 CO i-Bu H H H H CN 278 87 CO Ph H H H H CO₂CH₂CH₂CH₂NMe₂ 402 88 CO Ph H H H H

414 89 CHOH 2-furyl H H H H CN 290 90 CO Ph H H H H

414 91 CO Ph H H H H

430 92 CO Ph H H H H CO₂CH₂CHMeCH₂NMe₂ 416 93 CO 3-thiophenyl H H H H CO₂CH₂CH₂NMe₂ 394 94 CO CH₂CH₂CHCH₂ H H H H CN 276 95 CO c-Hex H H H H CN 302 (M − 1) 96 CO 2-furyl H H H H (S)—CO₂CHMeCH₂NMe₂ 392

III. Biological Assays and Activity Ligand Binding Assay for Adenosine A2a Receptor

Ligand binding assay of adenosine A2a receptor was performed using plasma membrane of HEK293 cells containing human A2a adenosine receptor (PerkinElmer, RB-HA2a) and radioligand [³H]CGS21680 (PerkinElmer, NET1021). Assay was set up in 96-well polypropylene plate in total volume of 200 μL by sequentially adding 20 μL1:20 diluted membrane, 130 μL assay buffer (50 mM Tris.HCl, pH7.4 10 mM MgCl₂, 1 mM EDTA) containing [³H] CGS21680, 50 μL diluted compound (4×) or vehicle control in assay buffer. Nonspecific binding was determined by 80 mM NECA. Reaction was carried out at room temperature for 2 hours before filtering through 96-well GF/C filter plate pre-soaked in 50 mM Tris.HCl, pH7.4 containing 0.3% polyethylenimine. Plates were then washed 5 times with cold 50 mM Tris.HCl, pH7.4, dried and sealed at the bottom. Microscintillation fluid 30 μl was added to each well and the top sealed. Plates were counted on Packard Topcount for [³H]. Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Varani, K.; Gessi, S.; Dalpiaz, A.; Borea, P. A. British Journal of Pharmacology, 1996, 117, 1693)

Adenosine A2a Receptor Functional Assay

CHO-K1 cells overexpressing human adenosine A2a receptors and containing cAMP-inducible beta-galactosidase reporter gene were seeded at 40-50K/well into 96-well tissue culture plates and cultured for two days. On assay day, cells were washed once with 200 μL assay medium (F-12 nutrient mixture/0.1% BSA). For agonist assay, adenosine A2a receptor agonist NECA was subsequently added and cell incubated at 37° C., 5% CO₂ for 5 hrs before stopping reaction. In the case of antagonist assay, cells were incubated with antagonists for 5 minutes at R.T. followed by addition of 50 nM NECA. Cells were then incubated at 37° C., 5% CO₂ for 5 hrs before stopping experiments by washing cells with PBS twice. 50 μL 1× lysis buffer (Promega, 5× stock solution, needs to be diluted to 1× before use) was added to each well and plates frozen at −20° C. For β-galactosidase enzyme colorimetric assay, plates were thawed out at room temperature and 50 μL 2× assay buffer (Promega) added to each well. Color was allowed to develop at 37° C. for 1 h or until reasonable signal appeared. Reaction was then stopped with 150 μL 1M sodium carbonate. Plates were counted at 405 nm on Vmax Machine (Molecular Devices). Data was analyzed in Microsoft Excel and GraphPad Prism programs. (Chen, W. B.; Shields, T. S.; Cone, R. D. Analytical Biochemistry, 1995, 226, 349; Stiles, G. Journal of Biological Chemistry, 1992, 267, 6451)

Haloperidol-Induced Catalepsy Study in C57bl/6 Mice

Mature male C57bl/6 mice (9-12 week old from ACE) were housed two per cage in a rodent room. Room temperature was maintained at 64-79 degrees and humidity at 30-70% and room lighting at 12 hrs light/12 hrs dark cycle. On the study day, mice were transferred to the study room. The mice were injected subcutaneously with haloperidol (Sigma H1512, 1.0 mg/ml made in 0.3% tartaric acid, then diluted to 0.2 mg/ml with saline) or vehicle at 1.5 mg/kg, 7.5 ml/kg. The mice were then placed in their home cages with access to water and food. 30 minutes later, the mice were orally dosed with vehicle (0.3% Tween 80 in saline) or compounds at 10 mg/kg, 10 ml/kg (compounds, 1 mg/ml, made in 0.3% Tween 80 in saline, sonicated to obtain a uniform suspension). The mice were then placed in their home cages with access to water and food. 1 hour after oral dose, the catalepsy test was performed. A vertical metal-wire grid (1.0 cm squares) was used for the test. The mice were placed on the grid and given a few seconds to settle down and their immobility time was recorded until the mice moved their back paw(s). The mice were removed gently from the grid and put back on the grid and their immobility time was counted again. The measurement was repeated three times. The average of three measurements was used for data analysis.

Compound 70 showed 87% inhibition and compound 3 showed 90% inhibition of haloperidol-induced catalepsy when orally dosed at 10 mg/kg.

TABLE 5 Ki (nM) A2a A1 A2a antagonist antagonist No. binding function function 1 44.64 233.7 52.98 2 2.032 6.868 5.32 3 0.26 0.0066 0.288 4 0.885 2.63 15.57 5 5.355 9.64 27.1 6 3.9 4.56 16.44 7 0.26 0.49 6.89 8 58.41 5.5 11.59 9 20.82 4.85 7.69 10 6.1 0.109 1.2 11 8.85 1.63 2.47 12 33.49 32.52 172.3 13 5.16 35.59 10.35 14 2.19 0.59 3.19 15 3.23 0.258 3.46 16 1.75 0.169 5.22 17 6.3 67.14 111.29 18 317.95 >3000 188.99 19 110.73 20.88 21.64 20 0.05 0.126 0.91 21 0.376 0.053 3.51 22 14.16 0.055 2.75 23 13.58 0.55 1.47 24 30.32 >3000 5.99 25 172.85 5.69 17.44 26 34.57 0.88 3.13 27 146.84 68.28 >1000 28 48.9 3.53 5.86 29 20.95 1.42 4.27 30 31.55 10.15 4.05 31 140.68 15.22 17.5 32 3.55 0.634 9.89 33 0.175 0.34 0.021 34 560.13 35 3.49 0.265 7.09 36 4.37 0.052 2.52 37 2.86 0.143 3.07 38 2.34 0.956 9.44 39 4.92 0.926 2.31 40 2720.46 41 88.01 575.43 >3000 42 118.2 782.18 >10000 43 39.9 3.68 2.34 44 3.93 0.208 7.4 45 4.013 0.005 0.016 46 60.56 490.14 32.54 47 1076.76 48 470.84 >1000 >1000 49 51.12 40.13 119.03 50 80.15 11.31 94.24 51 36.81 3.26 32.92 52 94.41 18.33 107.17 53 64.15 14.25 40.82 54 40.79 3.19 19.56 55 32.82 5.84 19.86 56 25.72 6.81 25.76 57 34.02 15.93 39.29 58 30.65 11.65 60.99 59 40.79 7.94 34.11 60 34.29 61 29.83 62 58.39 63 0.59 0.0002 0.18 64 13.09 0.138 4.61 65 574.71 244.96 163.36 66 4.21 0.069 15.59 67 13.4 0.618 4.37 68 7.59 0.73 34.84 69 2261 90.16 >1000 70 9.89 0.44 20.13 71 17.24 3.39 2.42 72 12.64 2.54 6.24 73 4.925 0.06 9.7 74 14.67 5.7 7.28 75 23.72 1.51 78.33 76 33.03 22.13 >500 77 6.254 0.68 >500 78 17.65 1.58 >500 79 8.03 12.48 >1000 80 69.08 15.86 55.99 81 228.7 29.03 33.63 82 20.24 1.36 29.58 83 200.06 74.87 117.05 84 173.98 24.71 27.42 85 507.72 86 244.07 >1000 39.26 87 98.93 39.45 >300 88 129.6 48.87 >300 89 5.85 1.12 11.16 90 202.17 57.7 >300 91 208.32 22.07 14.67 92 38.82 13.9 32.88 93 64.05 23.57 104.31 94 49.55 >1000 35.99 95 338.13 >1000 110.22 96 48.55 10.08 52.45 

1. A compound having the structure of Formula I or II

or a pharmaceutically acceptable salt thereof, wherein (a) R₁ is selected from the group consisting of (i) —COR₅, wherein R₅ is selected from H, optionally substituted C₁₋₈ straight or branched chain alkyl, optionally substituted aryl and optionally substituted arylalkyl; wherein the substituents on the alkyl, aryl and arylalkyl group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or NR₇R₈ wherein R₇ and R₈ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, or heteroaryl or NR₇R₈ taken together form a heterocycle or heteroaryl; (ii) COOR₅, wherein R₅ is as defined above; (iv) cyano; (v) —CONR₉R₁₀ wherein R₉ and R₁₀ are independently selected from H, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl, cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and heterocyclyl groups may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, amino, alkoxy or arylalkyl, or R₉ and R₁₀ taken together with the nitrogen to which they are attached form a heterocycle or heteroaryl group; (v) optionally substituted C₁₋₈ straight or branched chain alkyl; wherein the substituents on the alkyl, group are selected from C₁₋₈ alkoxy, phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, carboxyl, aryl, heterocyclyl, heteroaryl, sulfonyl, thiol, alkylthio, or NR₇R₈ wherein R₇ and R₈ are as defined above; (b) R₂ is selected from the group consisting of optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl and optionally substituted C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, aryloxy, C₁₋₈ alkylsulfonyl, arylsulfonyl, arylthio, C₁₋₈ alkylthio, or —NR₂₄R₂₅ wherein R₂₄ and R₂₅ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₂₄ and R₂₅ taken together with the nitrogen form a heteroaryl or heterocyclyl group, (c) R₃ is from one to four groups independently selected from the group consisting of: hydrogen, halo, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, aryl, heteroaryl, and heterocyclyl, —NR₁₁R₁₂, wherein R₁₁ and R₁₂ are independently selected from H, C₁₋₈ straight or branched chain alkyl, arylalkyl, C₃₋₇ cycloalkyl, carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R₁₀ and R₁₁ taken together with the nitrogen form a heteroaryl or heterocyclyl group, —NR₁₃COR₁₄, wherein R₁₃ is selected from hydrogen or alkyl and R₁₄ is selected from hydrogen, alkyl, substituted alkyl, C₁₋₃ alkoxyl, carboxyalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, R₁₅R₁₆N(CH₂)_(p)—, or R₁₅R₁₆NCO(CH₂)_(p)—, wherein R₁₅ and R₁₆ are independently selected from H, OH, alkyl, and alkoxy, and p is an integer from 1-6, wherein the alkyl group may be substituted with carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or R₁₃ and R₁₄ taken together with the carbonyl form a carbonyl containing heterocyclyl group; (d) R₄ is selected from the group consisting of hydrogen, C₁₋₆ straight or branched chain alkyl, benzyl wherein the alkyl and benzyl groups are optionally substituted with one or more groups selected from C₃₋₇ cycloalkyl, C₁₋₈ alkoxy, cyano, C₁₋₄ carboalkoxy, trifluoromethyl, C₁₋₈ alkylsulfonyl, halogen, nitro, hydroxy, trifluoromethoxy, C₁₋₈ carboxylate, amino, NR₁₇R₁₈, aryl and heteroaryl, —OR₁₇, and —NR₁₇R₁₈, wherein R₁₇ and R₁₈ are independently selected from hydrogen, and optionally substituted C₁₋₆ alkyl or aryl; and (e) X is selected from C═S, C═O; CH₂, CHOH, CHOR₁₉; or CHNR₂OR₂₁ where R₁₉, R₂₀, and R₂₁ are selected from optionally substituted C₁₋₈ straight of branched chain alkyl, wherein the substituents on the alkyl group are selected from C₁₋₈ alkoxy, hydroxy, halogen, amino, cyano, or NR₂₂R₂₃ wherein R₂₂ and R₂₃ are independently selected from the group consisting of hydrogen, C₁₋₈ straight or branched chain alkyl, C₃₋₇ cycloalkyl, benzyl, aryl, heteroaryl, or NR₂₂R₂₃ taken together from a heterocycle or heteroaryl; with the proviso that in a compound of Formula II when R₁ is a cyano, then R₂ is not phenyl.
 2. The compound of claim 1, formula I, wherein R₄ is amino.
 3. The compound of claim 1, formula I, wherein R₂ is aryl or heteroaryl.
 4. The compound of claim 1, formula II, wherein R₂ is aryl or heteroaryl.
 5. The compound of claim 4, wherein R₂ is furyl or substituted furyl.
 6. The compound of claim 4, wherein R₁ is COOR₅, wherein R₅ is selected from optionally substituted C₁₋₈ straight or branched chain alkyl.
 7. The compound of claim 1, which is 2-amino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one.
 8. The compound of claim 1, which is 2-amino-4-phenyl-indeno[1,2-d]pyrimidin-5-one.
 9. The compound of claim 1, which is 2-amino-4-thiophen-2-yl-indeno[1,2-d]pyrimidin-5-one.
 10. The compound of claim 1, which is 2-amino-4-(5-methyl-furan-2-yl)-indeno[1,2-d]pyrimidin-5-one.
 11. The compound of claim 1, which is 2,6-diamino-4-furan-2-yl-indeno[1,2-d]pyrimidin-5-one.
 12. The compounds of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carbonitrile, 3-amino-1-furan-2-yl-9-oxo-.
 13. The compound of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 2-dimethylamino-ethyl ester.
 14. The compound of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-phenyl-9-oxo-, 2-dimethylamino-ethyl ester.
 15. The compound of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-1-methyl-ethyl)-amide.
 16. The compound of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, (2-dimethylamino-ethyl)-methyl-amide.
 17. The compound of claim 1, which is 9H-indeno[2,1-c]pyridine-4-carboxylic acid, 3-amino-1-furan-2-yl-9-oxo-, 1-methyl-pyrrolidin-2-ylmethyl ester.
 18. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
 19. A method of treating a subject having a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, which comprises administering to the subject a therapeutically effective dose of the compound of claim
 1. 20. A method of preventing a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject, comprising administering to the subject a prophylactically effective dose of the compound of claim 1 either preceding or subsequent to an event anticipated to cause a disorder ameliorated by antagonizing Adenosine A2a receptors in appropriate cells in the subject.
 21. The method of claim 19 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim
 18. 22. The method of claim 20 comprising administering to the subject a therapeutically or prophylactically effective dose of the pharmaceutical composition of claim
 18. 23. The method of claim 19, wherein the disorder is a neurodegenerative disorder or a movement disorder.
 24. The method of claim 19, wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia.
 25. The method of claim 20, wherein the disorder is a neurodegenerative disorder or a movement disorder.
 26. The method of claim 20, wherein the disorder is selected from the group consisting of Parkinson's Disease, Huntington's Disease, Multiple System Atrophy, Corticobasal Degeneration, Alzheimer's Disease, and Senile Dementia. 